We are working on the identification, description, and treatment of congenital and acquired syndromes of increased susceptibility to infection. The syndromes in which we are interested primarily affect the phagocytes, and are most apparent in the increased susceptibility to nontuberculous mycobacteria. These organisms are important pathogens only in the immunocompromised host. Therefore, we have sought to identify patients without previously recognized forms of immunocompromise who have these infections and then determine the nature of their susceptibility. In this way we have identified previously and hope to further characterize the pathways involved in the control of mycobacteria and other intracellular pathogens, such as Salmonella. The abnormalities we have already identified center around macrophage/lymphocyte interactions leading to the production of or response to interferon gamma, IL-12, and tumor necrosis factor. In addition, the pathways regulating the response to tumor necrosis factor overlap with the interferon gamma signaling pathways and have been shown to be lesioned in patients with these infections. The study of these "experiments of nature" highlights the critical role of the macrophage/ lymphocyte interaction in control of mycobacteria and other intracellular pathogens. These observations have led us to explore cytokine therapies that may have broader application to the treatment of tuberculosis. Over the last year we have continued our focus on the regulation of inflammatory genes in mycobacterial infections through the study of the interferon gamma receptors. We have identified a new mutation in interferon gamma receptor 2, and extensively characterized the mechanisms of recycling and processing of the interferon gamma receptor 2. In addition, we have identified a large cohort of patients with significant autoimmunity involving interferon gamma.